Method and composition for treating an alpha adrenoceptor-mediated condition

ABSTRACT

Methods and compositions for the treatment of alpha-adrenoceptor mediated conditions.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority to co-pending U.S. Provisional PatentApplication Ser. No. 61/013,375, filed Dec. 13, 2007, which is herebyincorporated herein.

BACKGROUND OF THE INVENTION

1. Technical Field

This invention relates generally to the treatment of alpha-1adrenoceptor-mediated conditions.

2. Background

Alpha adrenoceptor-, and more specifically, alpha-1adrenoceptor-mediated conditions take a variety of forms, and aresuffered by a substantial subset of the population. Adrenoceptors (oradrenergic receptors) are a class of G protein-coupled receptors thatare targeted by catecholamines. They specifically bind, and are thusactivated by, their endogenous ligands, adrenaline (epinephrine) andnoradrenaline (norepinephrine). Alpha adrenoceptors bind norepinephrinewith a higher affinity than epinephrine. Alpha-1 adrenoceptors are foundin smooth muscle tissue, and mediate conditions including hypertension,congestive heart failure, cardiac hyperplasia, urethral obstruction,hyperinsulinemia, lipid disorders, ergot alkaloid poisoning,pheochromocytoma, Raynaud's disease, and male impotency. Some of theknown antagonists of alpha-1 adrenoceptors include phenoxybenzamine,phentolamine, prazosin, tamsulosin, and terazosin.

Benign prostatic hyperplasia (also referred to as benign prostatichypertrophy, or BPH) is a particularly common alpha-1adrenoceptor-mediated condition. It describes an enlargement of theprostate gland that frequently occurs as men age. The prostate glandcomprises two lobes enclosed by an outer layer of tissue, and is locatedin front of the rectum and just below the bladder, surrounding theurethra. Its primary function is the release of fluid during sexualclimax, assisting in the conduction of sperm through the urethra, andhelping to neutralize pH of the vaginal canal. (National Kidney andUrologic Diseases Information Clearinghouse (NKUDIC), NIH PublicationNo. 06-3012: Prostate Enlargement: Benign Prostatic Hyperplasia, athttp://kidney.niddk.nih.gov/kudiseases/pubs/prostateenlargement/index.htm#gland(June 2006) (last visited Oct. 26, 2006).)

Because of its proximity and position relative to the bladder andurethra, enlargement of the prostate gland may restrict the flow ofurine through the urethra. The layer of tissue surrounding the prostatelimits its expansion, causing the gland to press against the urethra,tending to narrow it and clamp it shut. The bladder wall subsequentlythickens and becomes irritated, and begins to contract even when itcontains only small amounts of urine (thereby causing frequenturination). Eventually, the bladder weakens and loses the ability toempty completely. This may lead to symptoms of a weak or interruptedurinary stream, a feeling of inability to completely empty the bladder,a feeling of delay or hesitation at the start of urination, a need tourinate frequently, especially at night, and a feeling of urgent need tourinate. (Id. athttp://kidney.niddk.nih.gov/kudiseases/pubs/prostateenlargement/index.htm#common.)

Drug treatment for BPH focuses on shrinking or preventing further growthor enlargement of the prostate without surgery. Six drugs are commonlyprescribed to alleviate clinical symptoms associated with an enlargedprostate, including Finasteride (PROSCAR), dutasteride (AVODART),terazosin (HYTRIN), doxazosin (CARDURA), tamsulosin (FLOMAX), andalfuzosin (UROXATRAL). Finasteride and dutasteride function byinhibiting production of the hormone DHT (dihydrotestosterone). TheMedical Therapy of Prostatic Symptoms (MTOPS) Trial, supported by theNational Institute of Diabetes and Digestive and Kidney Diseases(NIDDK), recently found that administration of finasteride and doxazosintogether is more effective than using either drug alone to relievesymptoms of BPH and prevent further enlargement.

Terazosin, doxazosin, tamsulosin, and alfuzosin, all belonging to theclass of drugs known as alpha-blockers, function by relaxing the smoothmuscle of the prostate and bladder neck, resulting in improved urineflow and reduced bladder outlet obstruction. (Id. athttp://kidney.niddk.nih.gov/kudiseases/pubs/prostateenlargement/index.htm#treatment.)Prazosin (MINIPRESS), an alpha-adrenergic blocker used for treatinghypertension, has also been found useful in treating BPH by blockingalpha-1 receptors, which control constriction of the prostate andureters. (MedlinePlus Drug Information: Prazosin (Systemic) athttp://www.nlm.nih.gov/medlineplus/druginfo/uspdi/202475.html (page lastupdated Oct. 13, 2006) (last visited Oct. 26, 2006).)

SUMMARY OF THE INVENTION

The invention provides methods and compositions for the treatment ofbenign prostatic hyperplasia (BPH) in a male mammal subject, including ahuman male, by internally administering to the subject an effectiveamount of4-[3-[4-(6-fluoro-1,2,-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxy-benzoicacid or a pharmaceutically acceptable salt thereof.

The illustrative aspects of the present invention are designed to solvethe problems herein described and other problems not discussed, whichare discoverable by a skilled artisan.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 shows concentration-response curves to phenylephrine (PE) in theabsence and presence of4-[3-[4-(6-fluoro-1,2,-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxy-benzoicacid at four different concentrations: (a) 0.1 uM, (b) 0.3 uM, (c) 1 uM,(d) 3 uM. Square points indicate PE before addition of the testsubstance and triangular points indicate PE after addition of the testsubstance.

FIG. 2 shows concentration-response curves to norepinephrine (NE) in theabsence and presence of4-[3-[4-(6-fluoro-1,2,-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxy-benzoicacid at four different concentrations: (a) 0.1 uM, (b) 0.3 uM, (c) 1 uM.Square points indicate NE before addition of the test substance andtriangular points indicate NE after addition of the test substance.

DETAILED DESCRIPTION

As indicated above, the invention provides methods for the treatment ofBPH. Such methods include the administration of an effective amount of4-[3-[4-(6-fluoro-1,2,-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxy-benzoicacid or a pharmaceutically acceptable salt thereof, alone or incombination with one or more additional active agents. These additionalactive agents may comprise one or more additional alpha-adrenoceptorantagonists, one or more steroid-5-alpha reductase inhibitors, or one ormore additional alpha adrenoceptor antagonists in combination with oneor more steroid-5-alpha reductase inhibitors.

As used herein, “effective amount” means an amount that prevents ordelays onset of signs and symptoms of the condition being treated for,or that eliminates or alleviates, i.e., lessens the severity or reducesthe frequency of occurrence, of signs and symptoms of the condition. Inaddition, “treatment,” “treating,” and “treat” shall mean treatment orprevention, i.e., the treatment or prevention of analpha-adrenoceptor-mediated condition.

The present invention contemplates use of4-[3-[4-(6-fluoro-1,2,-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxy-benzoicacid or a pharmaceutically acceptable salt thereof, as well as esters,solvates, hydrates, crystalline and amorphous forms, and polymorphsthereof.

4-[3-[4-(6-fluoro-1,2,-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxy-benzoicacid is a metabolite of Iloperidone. Iloperidone is disclosed in U.S.Pat. Nos. 5,364,866, 5,658,911, and 6,140,345, each of which isincorporated herein by reference. In some cases, it may be advantageousto use iloperidone or an iloperidone metabolite preferentially inpatients with certain genotypes as disclosed, e.g., in InternationalPatent Application Publication Nos. WO2006039663 and WO2003054226, whichare also incorporated herein by reference.

4-[3-[4-(6-fluoro-1,2,-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxy-benzoicacid has greatest affinity and is most potent for alpha 1 adrenoceptorsand the serotonin 5HT_(2A) receptor; it has slightly greateraffinity/potency for alpha 1 adrenoceptors than for alpha 2adrenoreceptors and has very weak if any activity with respect to thedopamine, histamine and serotonin receptors (other than 5HT_(2A)).

4-[3-[4-(6-fluoro-1,2,-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxy-benzoicacid appears not to cross the blood-brain barrier. Specifically, in DMPKstudies using rats treated with [140]4-[3-[4-(6-fluoro-1,2,-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxy-benzoicacid, none of the animals had measurable radioactivity concentrations inthe brain. Therefore,4-[3-[4-(6-fluoro-1,2,-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxy-benzoicacid is particularly useful in conditions that are not mediated, to asubstantial degree, by receptors in the brain.

A method according to the present invention includes administering to ananimal suffering from an enlarged prostate, or BPH, an effective amountof4-[3-[4-(6-fluoro-1,2,-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxy-benzoicacid or a pharmaceutically acceptable salt thereof.

4-[3-[4-(6-fluoro-1,2,-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxy-benzoicacid and pharmaceutically-acceptable salts thereof may be administeredseparately from or together with one or more additional alphaadrenoceptor antagonists. In such an embodiment, the one or moreadditional alpha adrenoceptor antagonist to be administered togetherwith4-[3-[4-(6-fluoro-1,2,-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxy-benzoicacid or a pharmaceutically acceptable salt thereof may be selected from:Doxazosin, e.g., CARDURA; Prazosin, e.g., MINIPRESS; Terazosin, e.g.,HYTRIN; Rec 15/2739; and tamsulosin, e.g., FLOMAX. Such an embodiment,for example, comprises a pill or capsule having both activepharmaceutical ingredients either admixed together or having each activepharmaceutical ingredient in a discrete portion of the pill or capsule.Metabolites, prodrugs, polymorphs, hydrates, solvates, and salts of theabove compounds that are directly or indirectly active can, of course,also be used in the practice of this invention.

In addition,4-[3-[4-(6-fluoro-1,2,-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxy-benzoicacid or a pharmaceutically-acceptable salt thereof, may beco-administered separately from or together with an effective amount ofone or more additional alpha-adrenoceptor antagonists, one or moresteroid-5-alpha reductase inhibitors, or one or more additional alphaadrenoceptor antagonists in combination with one or more steroid-5-alphareductase inhibitors. In this embodiment, the steroid-5-alpha reductaseinhibitor may be, for example, finasteride.

Compounds administered according to the invention may take any number offorms, including, for example, tablets, capsules, oral solutions,intravenous solutions, intramuscular injectables, intradermalinjectables, suppositories, patches, inhalents, and nasal sprays.Similarly, such compounds may be provided in immediate releaseformulations, extended release formulations, or long-term injectableformulations (e.g., 28 day depot formulations). In addition, methodsaccording to the invention may include once-, twice-, or thrice-dailyadministrations.

An effective amount of may be administered to a subject mammal(typically a human but other mammals, e.g., farm animals, pets andracing animals, can also be treated) by a number of routes. An effectiveamount is an amount that prevents or delays onset of signs and symptomsof enlargement of the prostate or that eliminates or alleviates, i.e.,lessens the severity or reduces the frequency of occurrence, of signsand symptoms of prostate enlargement. So, e.g., an effective amount isan amount that prevents, reverses, or slows prostate enlargement or thatalleviates the clinical symptoms of an enlarged prostate such as thesymptoms recited above.

An effective amount may vary quantitatively depending upon, e.g., thepatient, the severity of the disorder or symptom being treated, and theroute of administration. Such dose can be determined by routine studies.In general, for systemic administration, e.g., oral administration, aneffective amount is likely to be about 1 to about 500 mg/day, e.g.,about 5 to about 100 mg/day, or about 0.01 to about 10 mg/kg/day, e.g.,about 0.1 to about 5 mg/kg/day or about 0.5 to about 1.5 mg/kg/day.

It will be understood that the dosing protocol will be determined by aphysician in the light of the relevant circumstances. These include, forexample, the condition to be treated, the chosen route ofadministration, the age, weight, and response of the individual patient,and the severity of the patient's symptoms. Patients should of course bemonitored for possible adverse events.

For therapeutic or prophylactic use,4-[3-[4-(6-fluoro-1,2,-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxy-benzoicacid or pharmaceutically-acceptable salts thereof will normally beadministered as a pharmaceutical composition comprising, as the (or an)essential active ingredient, at least one such compound in associationwith a solid or liquid pharmaceutically acceptable carrier and,optionally, with pharmaceutically acceptable excipients employingstandard and conventional techniques.

Pharmaceutical compositions useful in the practice of this inventioninclude suitable dosage forms for oral, parenteral (includingsubcutaneous, intramuscular, intradermal and intravenous), transdermal,bronchial or nasal administration. Thus, if a solid carrier is used, thepreparation may be tableted, placed in a hard gelatin capsule in powderor pellet form, or in the form of a troche or lozenge. The solid carriermay contain conventional excipients such as binding agents, fillers,tableting lubricants, disintegrants, wetting agents and the like. Thetablet may, if desired, be film coated by conventional techniques. If aliquid carrier is employed, the preparation may be in the form of asyrup, emulsion, soft gelatin capsule, sterile vehicle for injection, anaqueous or non-aqueous liquid suspension, or may be a dry product forreconstitution with water or other suitable vehicle before use. Liquidpreparations may contain conventional additives such as suspendingagents, emulsifying agents, wetting agents, non-aqueous vehicle(including edible oils), preservatives, as well as flavoring and/orcoloring agents. For parenteral administration, a vehicle normally willcomprise sterile water, at least in large part, although salinesolutions, glucose solutions and like may be utilized. Injectablesuspensions also may be used, in which case conventional suspendingagents may be employed. Conventional preservatives, buffering agents andthe like also may be added to the parenteral dosage forms. Thepharmaceutical compositions may be prepared by conventional techniquesappropriate to the desired preparation containing appropriate amounts ofiloperidone or an active metabolite thereof. See, for example,REMINGTON'S PHARMACEUTICAL SCIENCES, Mack Publishing Company, Easton,Pa., 17th edition, 1985.

In making pharmaceutical compositions for use in the invention, theactive ingredient(s) will usually be mixed with a carrier, or diluted bya carrier, or enclosed within a carrier, which may be in the form of acapsule, sachet, paper, or other container. When the carrier serves as adiluent, it may be a solid, semi-solid, or liquid material which acts asa vehicle, excipient, or medium for the active ingredient. Thus, thecomposition can be in the form of tablets, pills, powders, lozenges,sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups,aerosols (as a solid or in a liquid medium), ointments containing forexample up to 10% by weight of the active compound, soft and hardgelatin capsules, suppositories, sterile injectable solutions, andsterile packaged powders.

Some examples of suitable excipients and diluents include lactose,dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calciumphosphate, alginates, tragacanth, gelatin, calcium silicate,microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water,syrup, methyl cellulose, methyl- and propylhydroxybenzoates, talc,magnesium stearate, and mineral oil. The formulations can additionallyinclude lubricating agents, wetting agents, emulsifying and suspendingagents, preserving agents, sweetening agents, and/or flavoring agents.The compositions of the invention may be formulated so as to providequick, sustained, or delayed release of the active ingredient afteradministration to the patient.

Administration of4-[3-[4-(6-fluoro-1,2,-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxy-benzoicacid or a pharmaceutically-acceptable salt thereof, according to any ofthe above embodiments, for treating BPH or for other indications, may beaccomplished through the use of a controlled release pharmaceuticaldosage form, e.g., delayed, sustained, or pulsatile release. By“controlled release” is meant that the absorption of the activepharmaceutical ingredient (API) is delayed, sustained or delayed andsustained relative to an immediate release oral form for administrationby swallowing. Such a dosage form is disclosed, e.g., in U.S. Pat. No.4,772,475, which is incorporated herein by reference.

For example, a controlled release formulation of the invention includesone in which:4-[3-[4-(6-fluoro-1,2,-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxy-benzoicacid or a pharmaceutically-acceptable salt thereof, dissolves at a rateof between about 3% and about 15% per hour, more preferably betweenabout 4% and about 13% per hour, and most preferably between about 5%and about 7% per hour in a standard dissolution assay (e.g., an aqueoussolvent at (1) pH 4.5, (2) pH 6.8 or (3) 0.1 N HCl, at 37 C), therebyproviding a slow, substantially constant dosage of4-[3-[4-(6-fluoro-1,2,-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxy-benzoicacid or a pharmaceutically acceptable salt thereof over a period ofbetween about 16 and about 24 hours. In another embodiment,4-[3-[4-(6-fluoro-1,2,-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxy-benzoicacid or a pharmaceutically acceptable salt thereof is released in apulsatile profile, e.g., to release approximately 25% of drug shortlyfollowing administration and approximately 25% of drug at more or less 2hours, 4 hours, and 6 hours post-administration, or to releaseapproximately 50% of drug shortly following administration andapproximately 25% of drug at more or less 2 hours and 4 hourspost-administration or to release approximately 50% of drug shortlyfollowing administration and approximately 25% of drug at more or less 4hours and 6 hours post-administration.

The controlled release dosage forms of the present invention may employa number of controlled release technologies for oral delivery. Forexample, Lalla and Bhat describe a method of coating DCP granules withthe vasodilator isosorbide dinitrate to slow its release. Such methodfor preparing a pharmaceutical composition of the present invention incontrolled release form comprises first spraying DCP granules with asugar syrup and sorting the coated granules to select those havingdiameters between about 500 and about 600 μm. Next, a coating of4-[3-[4-(6-fluoro-1,2,-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxy-benzoicacid or a pharmaceutically-acceptable salt or ester thereof (“activepharmaceutical ingredient” or “API”) is sprayed onto the surfaces of thegranules and the granules allowed to dry. A layer of an acidic bufferingagent can be applied under and/or above the drug layer in order tomaintain an acidic microenvironment in within the pellet matrix.Finally, a polymeric coating is applied to the dried API-coatedgranules. Alternatively, the dried granules may be pressed into atablet. See, J. K. Lalla & Shruti U. Bhat, Controlled-Release IsosorbideDinitrate Pellets. Part I: Design and Evaluation of Controlled-ReleaseCapsule Dosage Form, J. Pharm. Sci., 82(12):1288-1291 (1993); J. K.Lalla & Shruti U. Bhat, Controlled-Release Isosorbide Dinitrate Pellets.Part II: In Vivo Studies, J. Pharm. Sci., 82(12):1292-1295 (1993), bothof which are hereby incorporated by reference.

U.S. Pat. No. 5,968,554 to Beiman, et al. teaches a multi-layeredcontrolled release dosage capable of delivering a pharmaceutical to boththe stomach and the duodenum. Similarly, U.S. Pat. No. 6,312,728, alsoto Beiman, et al., teaches a multi-layered controlled release dosagecapable of delivering a pharmaceutical to both the duodenum and largeintestine or colon or to the stomach, duodenum, and large intestine orcolon. Both references are incorporated herein by reference.

A number of related controlled-release dosages and methods have beendescribed by Percel et al. For example, U.S. Pat. No. 6,627,223describes a pharmaceutical dosage comprised of timed, sustained-release(TSR) beads having at least two coated membrane barriers, thecomposition and thickness of the barriers determining the lag time andduration of drug release. In one embodiment, a first membrane barrier isan enteric polymer and a second membrane is a mixture of awater-insoluble polymer and an enteric polymer. Such a configurationpermits one or more pulses of a therapeutic agent in a plasmaconcentration-time profile.

U.S. Pat. No. 6,500,454, also to Percel et al., describes a dosage unitfor providing a circadian-like release of propranolol to mimic thetime-dependent physiological need for the drug. U.S. Pat. No. 6,663,888,also to Percel et al., describes a similar dosage for the circadian-likerelease of a histamine H2 antagonist. Each of the Percel et al.references above is incorporated herein by reference.

Other controlled-release methods known in the art are within the scopeof the present invention, including, for example, conventional pancoating, perforated pan coating, fluidized-bed coating, top-spraycoating, bottom-spray coating, and tangential-spray coating. See, e.g.,Atul M. Mehta & David M. Jones, Coated Pellets Under the Microscope,Pharm. Tech., June 1985, which is also hereby incorporated by reference.Various excipients may be incorporated into the controlled-releasedosage form of the invention. Such excipients include, for example,Eudragit® polymers (Rohm & Haas), ethylcellulose, Ethocel® polymers (DowChemical Company), triethyl citrate, hydroxypropyl methylcellulose(HPMC), polyvinylpyrrolidone (PVP), sugars, and acidic buffering agents.Generally, such excipients would comprise the bulk of acontrolled-release dosage.

In an alternative illustrative embodiment, a controlled release dosageform of the invention is designed to provide intermittent, or pulsatile,release of drug. In such embodiment, the dosage form may release 2, 3,4, 5, or even 6 aliquots of drug over a period of several hours, e.g.,2-24 hours, 8-24 hours, or 16-24 hours. An illustrative pulsatiledelivery dosage form of the invention releases drug in 3 aliquots, eachin a separate “compartment,” one that releases drug primarily in theduodenum, a second that releases drug primarily in the jejunum, and athird that releases drug primarily in the ileum. The amount of drugreleased in each aliquot can be an equal fraction of the total amount orthe amounts can be different. In pulsatile release embodiments of thisinvention, the choice of buffering agent and counterion can differ forthe different aliquots, depending, for example, on where in the GI tracta particular aliquot is expected to be released.

Various formulations and methods of administering iloperidone have beendescribed. For example, PCT Publication No. WO 2004/006886 A2 describesan injectable depot formulation comprising iloperidone crystals;microencapsulated depot formulations of iloperidone and a polyglycolidepolylactide glucose star polymer are described in U.S. PatentApplication Publication No. 20030091645; and methods for theadministration of iloperidone directed toward, inter alia, eliminatingor minimizing the prolongation of a corrected electrocardiographic QT(QTc) interval associated with increased concentrations of iloperidoneor iloperidone derivatives are described in U.S. Provisional PatentApplication No. 60/614,798, filed 30 Sep. 2004, all of which areincorporated herein by reference.

In another illustrative embodiment, the invention comprisesco-administering4-[3-[4-(6-fluoro-1,2,-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxy-benzoicacid and one or more additional alpha adrenoceptor antagonists, one ormore steroid-5-alpha reductase inhibitors, or a combination of one ormore additional alpha adrenoceptor antagonists and one or moresteroid-5-alpha reductase inhibitors at approximately the same time orat different time intervals, such that an effective amount of each ismaintained in the patient's bloodstream in the appropriate amounts atthe appropriate times.

In a related embodiment, a kit comprises pharmaceutical dosage units ofone agent alone, e.g.,4-[3-[4-(6-fluoro-1,2,-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxy-benzoicacid, and other pharmaceutical dosage units comprising a different orboth agents. Such a kit could facilitate, e.g., administration of thealpha adrenoceptor antagonist to be taken at different time intervalsthan the one or more additional alpha adrenoceptor antagonists, one ormore steroid-5-alpha reductase inhibitors, or the combination of one ormore additional alpha adrenoceptor antagonists and one or moresteroid-5-alpha reductase inhibitors.

When used in such combinations, the dose of each agent is expected to beapproximately the same as, or less than, an effective amount of eitheralone. For example, each pharmaceutically active ingredient can beadministered in doses that are about 20% to about 80% of the dose inwhich each ingredient would be administered alone.

The two (or more) agents can be administered more or lesssimultaneously, i.e., concomitantly (e.g., within about 0 to about 5minutes of each other, preferably within about a minute apart), or theycan be administered at different times. For example, the compositionscan be formulated in a unit dosage form, each dosage containing bothactive ingredients. The term “unit dosage form” refers to physicallydiscrete units suitable as unitary dosages for human subjects and otheranimals, each unit containing a predetermined quantity of activematerial calculated to produce the desired prophylactic or therapeuticeffect over the course of a treatment period, in association with therequired pharmaceutical carrier.

Unit dosage forms of the invention, whether they comprise4-[3-[4-(6-fluoro-1,2,-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxy-benzoicacid or a pharmaceutically-acceptable salt thereof as the sole activepharmaceutical ingredient or in combination with another agent, can alsobe formulated in a controlled release form, e.g., delayed, sustained, orpulsatile release. With such form, in the case of combinations,4-[3-[4-(6-fluoro-1,2,-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxy-benzoicacid or a pharmaceutically-acceptable salt thereof can be released atthe same or different rates and times as the other agent or agents.

In a related aspect, this invention comprises a method of promoting,marketing, or selling a pharmaceutical composition comprising4-[3-[4-(6-fluoro-1,2,-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxy-benzoicacid or a pharmaceutically-acceptable salt thereof that comprisesdisseminating information to prospective patients, formulary managers,or physicians or other prescribers about the compound, such informationincluding that4-[3-[4-(6-fluoro-1,2,-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxy-benzoicacid or a pharmaceutically-acceptable salt thereof is an alpha1adrenoceptor antagonist. Such information may also include that thecompound has been shown to be useful in the treatment of prostateenlargement, or BPH. In a related aspect, the invention comprises asystem for disseminating such information, such system comprising, forexample, a data storage medium wherein such information is stored, ameans for retrieving such information from the data storage medium, suchas a computer, and a means for disseminating the retrieved informationto relevant persons, such as by sending the information electronicallyor by printing and physically distributing copies of the printedinformation.

EXAMPLES

The following examples are illustrative and not limiting. Allexperiments described hereinbelow were conducted under the supervisionof Dr. Stefano Palea of UROsphere in Toulouse, France.

Example 1

The purpose of this example was to evaluate the effects of the testsubstance, i.e.,4-[3-[4-(6-fluoro-1,2,-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxy-benzoicacid, on phenylephrine (PE)-induced contraction in the prostatic smoothmuscle of male rabbits.

It is well established in the literature that the rabbit is a good modelfor the pharmacology of the lower urinary tract. In particular, acorrelation was found between affinities for clonedalpha1a-adrenoceptors and antagonist potency (pK_(b)) values for severalalpha1-adrenoceptors antagonists in the rabbit isolated prostate (Martinet al., J. Pharmacol. Expr. Ther. 282: 228-35, 1997).

Briefly, following animal sacrifice, transverse preparations of theprostate were suspended vertically in 25 mL glass organ baths under aloading tension of 1 g and placed in an oxygenated, modified Krebssolution (NaCl 114 mM, KCl 4.7 mM, CaCl₂ 2.5 mM, KH₂PO₄ 1.2 mM, NaHCO₃25 mM, glucose 11.7 mM (pH 7.4, gassed with 95% O₂ and 5% CO₂ at 37°C.). Propranolol (1 μM), desipramine (0.1 μM), deoxycorticosterone (3μM) and normetanephrine (1 μM) were added to the Krebs-Henseleitsolution in order to block beta-adrenoceptors, neuronal andextraneuronal uptake and catechol-O-methyl transferase, respectively.

After 60 min of equilibration, smooth muscle strips were exposed to 30μM PE to measure their viability. Strips having low contractileresponses (<0.5 g) were discarded. Following a 30 min washout period, afirst concentration-response curve (CRC) to PE (in the range 0.1 μM-1mM) was obtained by cumulative additions as half-log unit concentrationsincrements. Then, tissues were washed for 60 min and incubated for 60min with the test substance (at four different concentrations) before asecond PE CRC was obtained (in the range 0.1 μM-10 mM). Only oneconcentration for the test substance was tested on each single smoothmuscle strip. In different strips, a single concentration of tamsulosin(0.01 μM) was tested as a reference compound.

In this experiment, the pK_(b) value for alfuzosin was 7.25, a valuesimilar to the corresponding pK_(b) value found for the same antagoniston human isolated prostatic adenoma obtained from BPH patients (7.78,Palea et al., Neurourol. Urodyn. 19 (Suppl.): 431-33, 2000).

Mean values of the contractile response to 30 μM PE failed todemonstrate a significant statistical difference (p=0.0678 byKruskall-Wallis test).

The maximal response (Emax) value of the CRCs to PE following 60 minincubation (with a common solvent for4-[3-[4-(6-fluoro-1,2,-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxy-benzoicacid or tamsulosin) was significantly lower than the corresponding valueobtained before incubation (137.7% vs. 166.2%; p=0.005). However, thiswas not the case in the presence of the test substance at 0.1, 0.3 and 1μM demonstrating that, in the rest of the experiments, two consecutiveCRC to PE on the rabbit prostate were perfectly reproducible.

4-[3-[4-(6-fluoro-1,2,-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxy-benzoicacid concentration-dependently antagonized the PE-induced contractions(n=6 for each dose). See, FIG. 1. The −log EC50 (pEC50) values for PEbefore antagonist incubation were significantly different from pEC50values obtained in the presence of each4-[3-[4-(6-fluoro-1,2,-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxy-benzoicacid concentration or tamsulosin at 0.01 μM. Emax values were unaffectedby the presence of the two antagonists. (EC50 is the concentrationrequired to obtain 50% of a biological effect.)

The antagonist potency (pA₂, i.e., “minus one times the concentration ofantagonist causing the agonist to double its concentration in order toobtain the same effect) for4-[3-[4-(6-fluoro-1,2,-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxy-benzoicacid, estimated by the Schild plot, was equal to 7.47. The pA₂ fortamsulosin, calculated from the dose-ratio of pEC50 values, was equal to10.21, which is in accordance with a previous report on the rabbitisolated prostate (pK_(b)=9.74; Martin et al., 1997).

Based on the similar pEC50 values for PE in the presence of tamsulosinat 0.01 μM (2.65) and4-[3-[4-(6-fluoro-1,2,-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxy-benzoicacid at 3 μM (2.35), it is estimated that, on this rabbit preparation,tamsulosin is 300 times more potent than4-[3-[4-(6-fluoro-1,2,-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxy-benzoicacid.

These results showed that4-[3-[4-(6-fluoro-1,2,-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxy-benzoicacid is a functional antagonist of the alpha1-adrenoceptors activated byPE on the rabbit isolated prostatic smooth muscle. Its potency(pA₂=7.47) is approximately equal (Martin et al., 1997) to the potenciesshown by alpha1-adrenoceptor antagonists on the market for the treatmentof BPH, e.g. alfuzosin, doxazosin and terazosin.

Example 2

The purpose of this experiment was to evaluate the effects of4-[3-[4-(6-fluoro-1,2,-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxy-benzoicacid on norepinephrine (NE)-induced contraction in the prostatic adenomaobtained from patients affected by benign prostatic hyperplasia (BPH).

The experimental protocol used in this example is similar to the onedescribed in a previous paper to measure the antagonistic potency oftamsulosin (Noble et al., Br. J. Pharmacol. 120: 231-38, 1997).

Briefly, human prostatic adenoma was obtained from 6 patients (mean age71±5 years) undergoing transvesical adenomectomy of the prostate becauseof BPH. Prostatic strips were mounted in glass organ baths containing amodified Krebs-Henseleit solution (NaCl 114 mM, KCl 4.7 mM, CaCl₂ 2.5mM, KH₂PO₄ 1.2 mM, NaHCO₃ 25 mM, glucose 11.7 mM, ascorbic acid 1.1 mM(pH 7.4, gassed with 95% O₂ and 5% CO₂ at 37° C.) under 1.5 g tension.After 60 min of equilibration, the strips were exposed to 30 μM NE tomeasure their viability. Strips having a contractile response <0.3 gwere discarded.

After washout and 60 min of re-equilibration to re-establish baselinetension, a first cumulative concentration-response curve to NE (in therange 0.1 μM-1 mM) was constructed until a plateau of contraction wasreached. After 60 min washout to re-establish baseline tension, the testsubstance,4-[3-[4-(6-fluoro-1,2,-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxy-benzoicacid, at 0.1, 0.3 and 1 μM or the reference substance (tamsulosin) at0.01 μM for the two substances were incubated for 60 min, then a secondCRC to NE was constructed. Only one concentration of antagonist wastested in a single strip. Controls were obtained incubating strips for60 min with the common solvent (DMSO) for4-[3-[4-(6-fluoro-1,2,-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxy-benzoicacid and tamsulosin. The quantity of DMSO in the organ baths was equalto 0.1%.

Mean values of the contractile response to 30 μM NE failed todemonstrate a statistically significant difference (p>0.05 by ANOVAone-way).

The pEC50 value of the second CRC to NE was significantly lower(4.72+/−0.088) than the corresponding value obtained in the first CRC(5.17+/−0.088; p<0.001).

Incubation with4-[3-[4-(6-fluoro-1,2,-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxy-benzoicacid induced concentration-dependent shift in pEC50 of the second CRC toNE, indicating an antagonistic activity, but no effect on Emax values.NE pEC50 values were 4.15+/−0.11 (n=8), 3.69+/−0.24 (n=8), and3.26+/−0.08 (n=9) in the presence of the test substance at 0.1, 0.3, and1 uM, respectively. See, FIG. 2.

Dose-ratios obtained were corrected by the dose-ratio obtained in thegroup treated with the solvent. The pA₂ for4-[3-[4-(6-fluoro-1,2,-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxy-benzoicacid, estimated by the Schild Plot was equal to 7.50.

Incubation with 0.01 μM tamsulosin also induced a shift of the secondCRC to NE, indicating an antagonistic activity, but no effect on theEmax value. In the presence of tamsulosin, NE pEC50 was 2.96+/−0.20(n=8).

Following incubation with the solvent (0.1% DMSO) we observed a shift ofthe second CRC to NE. This result was unexpected since it was previouslyreported that NE did not induce desensitization of alpha1-adrenoceptorsin human isolated prostatic adenoma (Bagot et al., 2005). The onlyexplanation we can advance for this result is an inhibitory effect of 60min incubation with 0.1% DMSO.

The pA₂ of4-[3-[4-(6-fluoro-1,2,-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxy-benzoicacid (7.50) is in accordance with the value previously found on therabbit isolated prostate. The functional potency of4-[3-[4-(6-fluoro-1,2,-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxy-benzoicacid is also quite similar to pIC50 values obtained in binding studiesusing the rat alpha1A-adrenoceptor or the cloned human alpha1D-adrenoceptor (pIC50=7.94 and 7.75, respectively; data communicated byDr. Baroldi, Vanda Pharmaceuticals). Importantly, it is recognized thatblockade of both alpha1A- and alpha1 D-adrenoceptors is necessary foroptimal clinical effect on BPH patients (Andersson K E, World J. Urol.19: 390-96, 2002).

The comparison between the antagonistic potencies of4-[3-[4-(6-fluoro-1,2,-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxy-benzoicacid and tamsulosin shows that4-[3-[4-(6-fluoro-1,2,-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxy-benzoicacid is approximately 100 times less potent than tamsulosin on the humanalpha1-adrenoceptors expressed in the prostatic adenoma.

This example shows that4-[3-[4-(6-fluoro-1,2,-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxy-benzoicacid is a functional antagonist of the alpha1-adrenoceptors activated byNE on the human adenoma isolated from BPH patients. Its potency isapproximately equal to potencies published for some alpha1-adrenoceptorantagonists widely used in US for the treatment of BPH, e.g. alfuzosin,doxazosin, and terazosin.

Example 3

An experiment was conducted to evaluate the effect of4-[3-[4-(6-fluoro-1,2,-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxy-benzoicacid on PE-induced increase in intra-urethal pressure (UP) inanesthetized rats. Briefly, catheters were inserted into the femoralvein of anesthetized male rats for drug administration and into theurethra through the bladder wall for measuring urethral pressure (UP).The test substance, or tamsulosin, was administered 5 minutes beforeadministration of the first dose of PE. The different doses of PE(between 3 and 300 ug/kg in controls and up to 3000 ug/kg in treatedanimals) were administered intravenously under a volume of 1 mL/kg as abolus with a 3 minute interval between each dose. Three doses of testsubstance were used: 10, 33.3 and 100 ug/kg; one dose of tamsulosin: 10ug/kg; one control group (DMSO 1%).

In the presence of test substance, the dose response curve to PE wasdose-dependently shifted to the right. Test substance at 10 ug/kg i.v.showed a statistically significant inhibitory effect on the delta UP(over baseline) induced by 100 ug/kg PE. Test substance at 33.3 ug/kgi.v. showed a statistically significant inhibitory effect on the deltaUP (over baseline) induced by 30-100 and 150 ug/kg PE. Test substance at100 ug/kg i.v., and tamsulosin at 10 ug/kg, produced a statisticallysignificant decrease of the agonist effect in the dose range between 10and 300 ug/kg.

Therefore, in this study, by intravenous route,4-[3-[4-(6-fluoro-1,2,-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxy-benzoicacid is approximately 10 times less potent than tamsulosin inanesthetized rats. It has been previously shown that alfuzosin(UroXatral®) one of the most prescribed drugs for the treatment of BPH,was 10-fold less potent than tamsulosin (i.v.) in decreasing basalurethral pressure in conscious rats (Martin et al, J. Pharmacol. Exper.Ther. 282: 228-35, 1997).

Example 4

An experiment was conducted to evaluate the antagonistic effect of4-[3-[4-(6-fluoro-1,2,-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxy-benzoicacid on the PE-induced increase in intraurethral pressure (UP) andarterial blood pressure (BP) in anesthetized rats. Oral administrationof4-[3-[4-(6-fluoro-1,2,-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxy-benzoicacid or tamsulosin, had no effect on the basal UP measured 25 or 45minutes later. However, both4-[3-[4-(6-fluoro-1,2,-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxy-benzoicacid and tamsulosin significantly decreased the basal BP levels 25 and45 minutes after administration.

4-[3-[4-(6-fluoro-1,2,-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxy-benzoicacid at 0.5 mg/kg p.o. was ineffective on PE-induced increase of basalUP whereas it had a slight effect at 1.5 and 4.5 mg/kg. Doses of PEincreasing baseline UP or BP by 10, 25, 50, 75 and 100% suggest that,for4-[3-[4-(6-fluoro-1,2,-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxy-benzoicacid, the dose of 1.5 m/kg p.o. is more active than one at 4.5 mg/kg. Infact, the UP100% value at 45 min reached the level of statisticalsignificance in the presence of4-[3-[4-(6-fluoro-1,2,-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxy-benzoicacid at 1.5 mg/kg but not at 4.5 mg/kg. At this time, the effect on BPwas also significant from BP10% to BP100% in the presence of4-[3-[4-(6-fluoro-1,2,-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxy-benzoicacid at 1.5 mg/kg, whereas no effect was noticed at 4.5 mg/kg.

These results also draw to the conclusion, based on the equipotenteffects of 1.5 mg/kg4-[3-[4-(6-fluoro-1,2,-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxy-benzoicacid at 45 min post-administration and 0.3 mg/kg tamsulosin, that4-[3-[4-(6-fluoro-1,2,-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxy-benzoicacid is about 5 times less potent than tamsulosin by oral route, on bothUP and BP.

For comparison, silodosin administered intraduodenally was 2.8 timesless potent than tamsulosin on UP in a similar experimental model onrats (Akiyama et al., Pharmacol. Exp. Ther. 291: 81-91, 1999).

In another experiment, the effect of a 1-week treatment with4-[3-[4-(6-fluoro-1,2,-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxy-benzoicacid, tamulosin, and a common vehicle on bladder outletobstruction-induced bladder dysfunction in rats was evaluated. Althoughtamsulosin is reported to have been shown to be positive in the modelemployed, in this experiment, tamsulosin was completely ineffective oncystometric parameters.4-[3-[4-(6-fluoro-1,2,-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxy-benzoicacid was also devoid of significant effect on all cystometric parametersbut significantly decreased the amplitude of unstable contractions.However, this latter effect was exclusively observed at the lowest dosetested (1 mg/kg/day). Tamsulosin and4-[3-[4-(6-fluoro-1,2,-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxy-benzoicacid were both devoid of effect on the bladder hypertrophy secondary tooutlet obstruction.

The foregoing description of various aspects of the invention has beenpresented for purposes of illustration and description. It is notintended to be exhaustive or to limit the invention to the precise formdisclosed, and obviously, many modifications and variations arepossible. Such modifications and variations that may be apparent to aperson skilled in the art are intended to be included within the scopeof the invention as defined by the accompanying claims.

1. A method for treating prostate enlargement in a male mammal thatcomprises administering to the mammal an effective amount of4-[3-[4-(6-fluoro-1,2,-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxy-benzoicacid or a pharmaceutically acceptable salt thereof.
 2. The method ofclaim 1 wherein the prostate enlargement is benign prostatichyperplasia.
 3. The method of claim 1, wherein the mammal is a human. 4.The method of claim 1, wherein the mammal is also treated with one ormore additional alpha adrenoceptor antagonists.
 5. The method of claim 4wherein the one or more additional alpha adrenoceptor antagonists areselected from doxazosin, prazosin, terazosin, Rec 15/2739, andtamsulosin.
 6. The method of claim 1, wherein the mammal is also treatedwith a second agent selected from: one or more additional alphaadrenoceptor antagonists; one or more steroid-5-alpha reductaseinhibitors; or one or more additional alpha adrenoceptor antagonists incombination with one or more steroid-5-alpha reductase inhibitors. 7.The method of claim 1, wherein the mammal is also treated withfinasteride.
 8. The method of claim 1, wherein the4-[3-[4-(6-fluoro-1,2,-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxy-benzoicacid or pharmaceutically acceptable salt thereof is in a controlledrelease pharmaceutical dosage form.
 9. The method of claim 1, whereinthe4-[3-[4-(6-fluoro-1,2,-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxy-benzoicacid or pharmaceutically acceptable salt thereof administered to theanimal is about 1 to about 500 mg/day.
 10. The method of claim 9 whereinthe amount of4-[3-[4-(6-fluoro-1,2,-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxy-benzoicacid or pharmaceutically acceptable salt thereof administered to theanimal is about 5 to about 100 mg/day.
 11. The method of claim 9 whereinthe amount of4-[3-[4-(6-fluoro-1,2,-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxy-benzoicacid or pharmaceutically acceptable salt thereof administered to theanimal is about 0.01 to about 10 mg/kg/day.
 12. The method of claim 9,wherein the amount of4-[3-[4-(6-fluoro-1,2,-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxy-benzoicacid or pharmaceutically acceptable salt thereof administered to theanimal is 0.5 to 1.5 mg/kg/day.
 13. A pharmaceutical composition thatcomprises4-[3-[4-(6-fluoro-1,2,-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxy-benzoicacid or a pharmaceutically acceptable salt thereof and apharmaceutically acceptable excipient.
 14. The pharmaceuticalcomposition of claim 13 that comprises an effective amount, in one ormore dosage units, for the treatment of BPH.
 15. The pharmaceuticalcomposition of claim 13 that is a controlled release formulation.